Congestive Heart Failure Dr Bernard Silke, MD, DSc, FRCP, Cardiovascular Physician, St. James’...

Congestive Heart FailureCongestive Heart Failure

Dr Bernard Silke, MD, DSc, FRCP,

Cardiovascular Physician,

St. James’ Hospital, Dublin 8.

Congestive Heart FailureCongestive Heart FailureChanging population trendsChanging population trends

No.(millions)

Rate per million

W. Europe 5.3 14000

E. Europe 1.3 13000

USSR 5.6 19000

N. America 5.2 18000

Japan 2.4 19000

Clinical ScenarioClinical Scenario

JB is 75 and is a retired publican. First presented 12 yr ago JB is 75 and is a retired publican. First presented 12 yr ago

with MI.with MI.

A strong family Hx of CVS disease. Father died at age 40 A strong family Hx of CVS disease. Father died at age 40

with Stroke. Mother had angina.with Stroke. Mother had angina.

Subsequent LVF 5 yr ago with hospitalization. Echo dilated / Subsequent LVF 5 yr ago with hospitalization. Echo dilated /

asymmetrical contraction / dysynergy.asymmetrical contraction / dysynergy.

Ejection Fraction 35%. Effort DyEjection Fraction 35%. Effort Dysspnoeapnoea

What are the therapeutic options?What are the therapeutic options?

Congestive Heart FailureCongestive Heart FailureIncidence and ageIncidence and age

Eur Heart J 1999: 20; 421-428.

0

4

8

12

16

Males

Females

55-64 65-74 75-84 85+Age group (yr)

Inci

den

ce p

er 1

000

pat

ien

t ye

ars


< 5% of population< 5% of population

CHF in 1.5% (25-75 yr)CHF in 1.5% (25-75 yr)

LV Systolic function LV Systolic function

abnormality in 1%abnormality in 1%

Clinical CHF - 1%Clinical CHF - 1%

Suspect CHF - 1%Suspect CHF - 1%

0

1

2

3

4

5

CH

F

LV

SD

Eit

he

r

Su

sp

ec

t


MI deaths peaked 1985 MI deaths peaked 1985

Rate 215 / 100,000Rate 215 / 100,000

Between 1985 - 1995 Between 1985 - 1995

mortality rates decrease mortality rates decrease

by 33% (215.3 - 144.2)by 33% (215.3 - 144.2)

Numbers of very elderly Numbers of very elderly

predicted to increase by predicted to increase by

30% and 57% over next 30% and 57% over next

two decadestwo decades

-50

-40

-30

-20

-10

0

10

60-64

70-74

80-85

Heart FailureHeart FailureDefinitionDefinition

Heart unable to meet peripheral blood flow Heart unable to meet peripheral blood flow

requirements without a rise in filling volumerequirements without a rise in filling volume

Contraction energy is reducedContraction energy is reduced

Stroke volume incompletely expelledStroke volume incompletely expelled

Chamber volume increasesChamber volume increases

Heart FailureHeart FailureNatural historyNatural history

0

100

Morbidity

0

100

MortalityNo symptoms

No deaths

Rest symptomsPump Failure

Time from onset

Heart FailureHeart FailureTherapeutic goalsTherapeutic goals

AI

A + V

V

D

Ventricular Filling Pressure

StrokeVolume

Normal

CHF

Heart FailureHeart FailureEjection FractionEjection Fraction

Ejection Fraction - % of Ejection Fraction - % of

EDV ejected each beatEDV ejected each beat

Normal 50 - 75%Normal 50 - 75%

Impaired function < 40%Impaired function < 40%

Symptomatic < 30%Symptomatic < 30%

If EDV 100 mlIf EDV 100 ml

Stroke volume 65 mlStroke volume 65 ml

CHF < 40 mlCHF < 40 ml

Heart FailureHeart FailureTherapeutic implicationsTherapeutic implications

Volume overload Volume overload

DiureticsDiuretics

Elevated impedance Elevated impedance

VasodilatorsVasodilators

Decreased contractility Decreased contractility

InotropesInotropes

Heart FailureHeart FailureClinical goalsClinical goals

Patient oedema freePatient oedema free

AmbulantAmbulant

Avoid hospitalisationAvoid hospitalisation

Optimise quality of lifeOptimise quality of life

Heart FailureHeart FailureClinical assessmentClinical assessment

Peripheral oedema – none to minimalPeripheral oedema – none to minimal

Paroxysmal nocturnal dyspnoea - infrequentParoxysmal nocturnal dyspnoea - infrequent

Posture at night - < 2 pillowsPosture at night - < 2 pillows

Dyspnoea – absent at rest, activity possibleDyspnoea – absent at rest, activity possible

Nocturia – common and not significantNocturia – common and not significant

Heart FailureHeart FailureTherapeutic groupsTherapeutic groups

DiureticsDiuretics

Thiazide group, LoopThiazide group, Loop diureticsdiuretics

Angiotensin converting enzyme inhibitorsAngiotensin converting enzyme inhibitors

Long-acting nitratesLong-acting nitrates

Captopril, Enalapril, Lisinopril, TrandoloprilCaptopril, Enalapril, Lisinopril, Trandolopril

InotropesInotropes

DigoxinDigoxin

Cortex

Medulla

ThiazidesInhibit active exchange of Cl-Na

in the cortical diluting segment of the ascending loop of Henle

K-sparingInhibit reabsorption of Na in the

distal convoluted and collecting tubule

Loop diuretics Inhibit exchange of Cl-Na-K in

the thick segment of the ascending loop of Henle

Loop of HenleCollecting tubule

DIURETICS

Heart Failure Heart Failure Diuretics : Sites of ActionDiuretics : Sites of Action

Glomerulus

ProximalTubule(CAI)

Na/K/Cl

AscendingLimb

(Loop)

Distal CT(Thiazides)

Na/Cl

AmilorideNa

Spironolactone

Na/K

CollectingDuct

Heart Failure Heart Failure Diuretics : Sites of ActionDiuretics : Sites of Action

Na/K/Cl

AscendingLimb

(Loop)

CollectingDuct

Tubular cellhypertrophy

Sodium loadto distal nephronincreased

Heart Failure Heart Failure Diuretics : ResistanceDiuretics : Resistance

Check complianceCheck compliance

Check NaCheck Na++ intake intake

Low salt dietLow salt diet

Avoid bread / processed foodsAvoid bread / processed foods

Daily fluid allowance 1LDaily fluid allowance 1L

Check not taking a NSAIDCheck not taking a NSAID

Increased dose of a loop diuretic?Increased dose of a loop diuretic?

Metolazone (pulse 2.5 mg) once / twice weekMetolazone (pulse 2.5 mg) once / twice week

Heart FailureHeart FailureACE InhibitorsACE Inhibitors

Prolong survival in early and established CHFProlong survival in early and established CHF

Improve Quality of LifeImprove Quality of Life

Relieve symptomatic congestionRelieve symptomatic congestion

Increase exercise toleranceIncrease exercise tolerance

Reduce hospitalisationReduce hospitalisation

Heart Failure Heart Failure Choice of ACE Inhibitor Choice of ACE Inhibitor

Captopril - first generationCaptopril - first generationShort duration of actionShort duration of action

Multiple dose administration (50 mg tds)Multiple dose administration (50 mg tds)

Enalapril, Lisinopril - second generationEnalapril, Lisinopril - second generationLonger duration of action (once daily)Longer duration of action (once daily)

Increased liklihood of hypotensionIncreased liklihood of hypotension

Perindopril, Trandolopril - third generationPerindopril, Trandolopril - third generationVascular selectiveVascular selective

Favourable side-effect profileFavourable side-effect profile

Lack of first-dose effectLack of first-dose effect

Placebo

Enalapril

12111098765

PROBABILITYOFDEATH

MONTHS

0.1

0.8

0

0.2

0.3

0.7

0.4

0.5

0.6p< 0.001

p< 0.002

CONSENSUSN Engl J Med 1987;316:1429

43210

Heart Failure Heart Failure Benefits of ACEIBenefits of ACEI

Heart Failure Heart Failure Benefits of ACEIBenefits of ACEI

50

40

30

20

10

0

Months0 6 12

p = 0.0036

%MORTALITY

2418 30 36 42 48

Enalapriln=1285

Placebon=1284

SOLVD (Treatment)N Engl J M 1991;325:293

n = 2589CHF - NYHA II-III- EF < 35

Heart Failure Heart Failure Contemporary management with ACEIContemporary management with ACEI

Considerable variations in ACE prescribingConsiderable variations in ACE prescribing

ACE Inhibitors used in 30 - 60% of CHF casesACE Inhibitors used in 30 - 60% of CHF cases

Elderly less likely to be treated (21 vs 69%)Elderly less likely to be treated (21 vs 69%)

Physician perceptions of contra-indicationPhysician perceptions of contra-indication

No documented contra-indications in 35%No documented contra-indications in 35%

Elderly high rate of morbid eventsElderly high rate of morbid events

Withhold ACE more complications (p < 0.01)Withhold ACE more complications (p < 0.01)

Am. Heart J. 1998:136;43.

Heart Failure Heart Failure Survival benefits & dosage (mg / day)Survival benefits & dosage (mg / day)

EnalaprilEnalapril

CaptoprilCaptopril

RamiprilRamipril

LisinoprilLisinopril

TrandolaprilTrandolapril

QuinaprilQuinapril

2020

150150

10 10

10 / 20 10 / 20

4 4

4040

Am. Heart J. 1998:136;43.

Heart Failure Heart Failure Contemporary issues & ACEIContemporary issues & ACEI

Pharmacodynamic response to ACEI elderlyPharmacodynamic response to ACEI elderly

Valid concerns hypotension / renal dysfunctionValid concerns hypotension / renal dysfunction

Reluctance to adequately dose titrateReluctance to adequately dose titrate

Many patients left on initiation dosageMany patients left on initiation dosage

Elderly patients will tolerate ACEI and achieve Elderly patients will tolerate ACEI and achieve

target doses if titrated graduallytarget doses if titrated gradually

Suboptimal RSuboptimal Rxx important due to high morbidity important due to high morbidity

Am. Heart J. 1998:136;43.

Heart Failure Heart Failure Contemporary management with ACEIContemporary management with ACEI

SPICE registry SPICE registry

Eight countriesEight countries

Hospital casesHospital cases

Consecutive 9581Consecutive 9581

Current practice Current practice

USA and EuropeUSA and Europe

Treated

Intolerant

High risk

Unknown

Recent82%

9%

4%2%

3%

Heart FailureHeart FailureACEI ADR profileACEI ADR profile

SPICE registry of 8485 casesSPICE registry of 8485 cases

Cough (308 - 4%)Cough (308 - 4%)

Renal sufficiency (188 - 2%)Renal sufficiency (188 - 2%)

Symptomatic hypotension (147 - 2%)Symptomatic hypotension (147 - 2%)

Hyperkalaemia (35)Hyperkalaemia (35)

Rash / pruritus (25)Rash / pruritus (25)

Angioedema / analyphaxis (19)Angioedema / analyphaxis (19)

Na+

K+

K+

Na+

Na+ Ca++

Ca++

Na-K ATPase Na-Ca Exchange

Myofilaments

DIGOXIN

CONTRACTILITY

Heart Failure Heart Failure Drug Therapy : DigoxinDrug Therapy : Digoxin

Positive InotropicPositive Inotropic

S-A and A-V Nodal actionsS-A and A-V Nodal actions

Enhanced AutomaticityEnhanced Automaticity

%WORSENING

OF CHFp = 0.001DIGOXIN: 0.125 - 0.5 mg /d

(0.7 - 2.0 ng/ml)EF < 35%Class I-III (digoxin+diuretic+ACEI)Also significantly decreased exercisetime and LVEF.

DIGOXIN EFFECT ON CHF PROGRESSION

RADIANCEN Engl J Med 1993;329:1

Placebo n=93DIGOXIN Withdrawal

DIGOXIN n=85

30

10

0

20

10080200 40 60Days

Heart Failure Heart Failure The DIG StudyThe DIG Study

CHF patients (6800) studied 1991 - 1995CHF patients (6800) studied 1991 - 1995

Sinus rhythm; E.F. < 45%Sinus rhythm; E.F. < 45%

NYHA Class III 33%; Class II < 50%NYHA Class III 33%; Class II < 50%

Background ACEI and/or diuretic (78%)Background ACEI and/or diuretic (78%)

Digoxin (median 250 ug / day) vs. placeboDigoxin (median 250 ug / day) vs. placebo

Endpoints: mortality and hospitalisationEndpoints: mortality and hospitalisation

N. Engl. J. Med. 1997: 336; 525

50

40

30

20

10

0

Placebon=3403

DIGOXINn=3397

480 12 24 36

OVERALL MORTALITY

%

DIG StudyN. Engl. J. Med. 1997: 336; 525 Months

p = 0.8


Mortality similar (34.8% vs. 35.1%)Mortality similar (34.8% vs. 35.1%)

Hospitalisations reduced 22% (16 - 28)Hospitalisations reduced 22% (16 - 28)

Benefits greatest in those at highest riskBenefits greatest in those at highest riskLower E.F. ( < 25% )Lower E.F. ( < 25% )

Enlarged heartsEnlarged hearts

NYHA Class III & IVNYHA Class III & IV

Digoxin toxicityDigoxin toxicityVentricular fibrillation / tachycardiaVentricular fibrillation / tachycardia

Supraventricular dysrhythmiaSupraventricular dysrhythmia

Second or 3rd degree heart blockSecond or 3rd degree heart block

N. Engl. J. Med. 1997: 336; 525


No substantial change in mortality /morbidityNo substantial change in mortality /morbidity

No ethical mandate for its useNo ethical mandate for its use

May be prescribed for symptomatic reliefMay be prescribed for symptomatic relief

Other drug categories have proven benefitOther drug categories have proven benefit

ACEI and ß-blockers drugs ACEI and ß-blockers drugs

N. Engl. J. Med. 1997: 336; 575

Heart Failure Heart Failure Digoxin TherapeuticsDigoxin Therapeutics

Atrial fibrillation with uncontrolled responseAtrial fibrillation with uncontrolled response

Reduce apex rate to 100 or less.Reduce apex rate to 100 or less.

Loading 15 ug / kg in three doses over 24 hrLoading 15 ug / kg in three doses over 24 hr

Maintenance dose 250 to 500 ug / dayMaintenance dose 250 to 500 ug / day

Therapeutic concentration 0.8 - 2.0 ng / mlTherapeutic concentration 0.8 - 2.0 ng / ml

Heart Failure Heart Failure ß ß - - blocking Therapyblocking Therapy

Reduce heart rate & myocardial contractilityReduce heart rate & myocardial contractility

Concern about risk of cardiac depressionConcern about risk of cardiac depression

In CHF ß - adrenoceptors are downregulatedIn CHF ß - adrenoceptors are downregulated

Cardiac efficiency impaired by compensationCardiac efficiency impaired by compensation

Upregulation during ß - blocking treatmentUpregulation during ß - blocking treatment

CIBIS I in 641 CHF - 20% mortality reductionCIBIS I in 641 CHF - 20% mortality reduction

Carvedilol(n=696)

Placebo(n=398)

Survival

Days0 50 100 150 200 250 300 350 400

1.0

0.9

0.8

0.7

0.6

0.5

Risk reduction=65%p<0.001

Packer et al (1996)Packer et al (1996)

CIBIS-II Investigators (1999)CIBIS-II Investigators (1999)

0 200 400 600 800

1.0

0.8

0.6

0

Bisoprolol

Placebo

Time after inclusion (days)

p<0.0001

Survival

Risk reduction=34%

The MERIT-HF Study Group (1999)The MERIT-HF Study Group (1999)

Months of follow-up

Mortality (%)

0 3 6 9 12 15 18 21

20

15

10

5

0

Placebo

Metoprolol CR/XL

p=0.0062

Risk reduction=34%

US Carvedilol Programme

blockers in blockers in heart failure –heart failure –

all-cause mortalityall-cause mortality

CIBIS-II MERIT-HF

Heart Failure Heart Failure ß ß - - blocking Therapyblocking Therapy

Over 13 000 patients evaluated in placebo-Over 13 000 patients evaluated in placebo-

controlled clinical trialscontrolled clinical trials

Consistent improvement in cardiac function, Consistent improvement in cardiac function,

symptoms and clinical statussymptoms and clinical status

Decrease in all-cause mortality by 30–35% Decrease in all-cause mortality by 30–35%

((pp<0.0001)<0.0001)

Decrease in combined risk of death and Decrease in combined risk of death and

hospitalisation by 25–30% (hospitalisation by 25–30% (pp<0.0001)<0.0001)

BackgroundBackground

Angiotensin II type 1 (AT1) receptor blockers (ARBs) provide a pharmacologically distinct mechanism of inhibiting the renin-angiotensin-aldosterone system

ARBs offer the potential to produce further clinical improvements above and beyond ACE inhibitors as well as an alternative for those previously intolerant to an ACE inhibitor

CHARM Added

CHARMPreserved

CHARM ProgrammeCHARM Programme

3 component trials comparing candesartan to placebo in patients with symptomatic heart failure

CHARMAlternative

n=2028

LVEF 40%ACE inhibitor

intolerant

n=2548


treated

n=3025

LVEF >40%ACE inhibitor

treated/not treated

Primary outcome for Overall Programme: All-cause death

Primary outcome for each trial: CV death or CHF hospitalisation

Study designStudy designDose-titration and visit scheduleDose-titration and visit schedule

32 mgCandesartan/matching placeboonce daily16 mg

8 mg 32 mg4 mg 16 mg8 mg

Time 0 w 2 w 4 w 6 w 6 mEvery 4 monthsuntil study end31 March 2003

Visit 1 2 3 4 5

Mean age (years) 67 64 67 66

Women (%) 32 21 40 32

NYHA class (%)II 48 24 60 45III 49 73 38 52IV 3 3 2 3

Mean LVEF 30 28 54 39

Medical history (%) myocardial infarction 61 56 44 53 diabetes 27 30 28 28 hypertension 50 48 64 55 atrial fibrillation 25 26 29 27

Baseline characteristics Baseline characteristics Alternative Added Preserved Overall

n=2028 n=2548 n=3023 n=7599

CHARM ProgrammeCHARM Programme

n=3025

LVEF >40% ACE inhibitor

treated/not treated

CHARM Added

CHARMPreserved

3 component trials comparingcandesartan to placebo

CHARMAlternative

n=2028


intolerant

n=2548


treated

Primary outcome:CV death or CHF hosp

CHARM-Alternative: Primary outcome CHARM-Alternative: Primary outcome CV CV deathdeath or CHF hospitalisation or CHF hospitalisation

%

Number at risk

Candesartan 1013 929 831 434 122

Placebo 1015 887 798 427 126

0 1 2 3 years0

10

20

30

40

50

Placebo

Candesartan

HR 0.77 (95% CI 0.67-0.89), p=0.0004Adjusted HR 0.70, p<0.0001

3.5

406 (40.0%)

334 (33.0%)

CHARM-Alternative CHARM-Alternative Investigator reported CHF hospitalisationsInvestigator reported CHF hospitalisations

0

5

10

15

20

25

30

35

0

100

200

300

400

500

600

700

PlaceboCandesartanProportion of

patients (%)

Patients hospitalised Hospitalisations

p<0.0001 p=0.0001

Number of episodes

CHARM-Alternative CHARM-Alternative Permanent study drug discontinuationsPermanent study drug discontinuations

0

5

10

15

20

25Percent of patients

PlaceboCandesartan

19.3

0.92.7

0.3 0.4

21.5

3.76.1

1.90.2

p=0.23 p<0.0001 p<0.0001 p=0.0005 p=0.69

Hypo-tension

Increased creatinine

Increasedpotassium

CoughAE/lab. abnorm.

0 0.1

p=0.50

Angio-edema

CHARM-AlternativeCHARM-AlternativeConclusionsConclusions

Despite prior intolerance to another inhibitor of the Despite prior intolerance to another inhibitor of the renin-angiotensin-aldosterone system, candesartan renin-angiotensin-aldosterone system, candesartan

was well toleratedwas well tolerated

In patients with symptomatic chronic heart failure In patients with symptomatic chronic heart failure and ACE-inhibitor intolerance, and ACE-inhibitor intolerance, candesartan candesartan reduces cardiovascular mortality and morbidity reduces cardiovascular mortality and morbidity

Cardioprotective Effects of Valsartan Cardioprotective Effects of Valsartan as Seen in the Valsartan-Heart Failure as Seen in the Valsartan-Heart Failure

Trial (Val-HeFT)Trial (Val-HeFT)

Jay N. Cohn, MDJay N. Cohn, MD

Professor of MedicineProfessor of Medicine

University of Minnesota Medical SchoolUniversity of Minnesota Medical School

Minneapolis, Minnesota, USA Minneapolis, Minnesota, USA

49

Study OverviewStudy Overview

5010 patients 18 years; EF <40%; NYHA II-IV; LVIDd >2.9 cm/m2

ACE inhibitors (92.7%), diuretics (85.8%),digoxin (67.3%), -blockers (35.6%)

Valsartan40 mg bid titrated to

160 mg bid

Randomized to

Receiving background therapy

Placebo

Cohn JN et al. Eur J Heart Fail. 2000;2:439-446.

Patients’ Baseline Patients’ Baseline CharacteristicsCharacteristics

Valsartan(n = 2511)

Placebo(n = 2499)

Mean age (y) 62.4 63.0

Gender, male (%) 79.9 80.0

Race (%)White 89.8 90.9

NYHA Class (%)II 62.1 61.4III 36.1 36.3IV 1.7 2.2

Ejection fraction (%) 26.6 26.9

Background therapy (%)Diuretic 85.8 85.2Digoxin 67.1 67.6-Blocker 34.5 35.3ACE inhibitor 92.6 92.8

Cohn JN et al. N Engl J Med. 2001;345:1667-1675.

Primary and Secondary Efficacy Primary and Secondary Efficacy Endpoints*Endpoints*

Combined all-cause mortality and Combined all-cause mortality and

morbidity (time to event) morbidity (time to event)

Hospitalization for heart failure Hospitalization for heart failure

Sudden death with resuscitationSudden death with resuscitation

Need for intravenous inotropes/vasodilators Need for intravenous inotropes/vasodilators

for worsening HFfor worsening HF

All-cause mortality (time to event)All-cause mortality (time to event)

Hospitalization for heart failureHospitalization for heart failure

Signs and symptoms of heart failureSigns and symptoms of heart failure

NYHA functional class (change from NYHA functional class (change from

baseline)baseline)

Echocardiographic indices of left Echocardiographic indices of left

ventricular function (LVEF and LVIDd ventricular function (LVEF and LVIDd

—— change from baseline) change from baseline)

Quality of life score (Minnesota Living Quality of life score (Minnesota Living

With Heart Failure score)With Heart Failure score)

*For the trial to be positive, one of the primary endpoints had to reach statistical significance (P < 0.02532).


Mortality and Morbidity AnalysesMortality and Morbidity Analyses

Primary Endpoint AnalysesPrimary Endpoint Analyses

Combined all- cause mortality and morbidity

Events

Valsartan(n = 2511)

Placebo(n = 2499) P Value

723(28.8%)

495(19.7%)

0.009*

0.80

801 (32.1%)

484 (19.4%)

13.2%

–

RR

0.87 (0.77-0.97)

1.02 (0.88-1.18)

Reduction

All-cause mortality

*Log-rank test.


Effect of Valsartan on Morbidity Effect of Valsartan on Morbidity Endpoint*Endpoint*

Months

3 6 9 12 15 18 21 24 270

65

70

75

80

85

90

95

100

Probability of Event-Free

Survival

0

*All-cause mortality, sudden death with resuscitation, hospitalization for worsening heart failure, or therapy with IV inotropes or vasodilators.


30

ValsartanPlacebo

P = 0.00913.2% Risk Reduction

All-Cause Mortality: All-Cause Mortality: Kaplan-Meier Analysis (Val-HeFT)* Kaplan-Meier Analysis (Val-HeFT)*

*P value (log-rank): 0.801; hazard ratio (Cox model): 1.017.Cohn JN et al. N Engl J Med. 2001;345:1667-1675.

Patients at RiskMonths 0 6 12 18 24 30Valsartan 2511 2389 2279 1779 1201 439Placebo 2499 2370 2260 1784 1196 440

ValsartanPlacebo

Time Since Randomization (mo)

Proportion Survived

0 3 6 9 12 15 18 21 24 27 30

1.0

0.9

0.8

0.7

0.6

0.5

Favors PlaceboFavors Valsartann

Mortality by ACE Inhibitor/Beta Blocker Mortality by ACE Inhibitor/Beta Blocker SubgroupsSubgroups

ACEI - 366ACEI + 4644BB - 3260BB + 1750

ACEI - BB - 226ACEI - BB + 140ACEI + BB - 3034ACEI + BB + 1610

0.4 0.6 1.0 1.2 1.8 2.00.2 0.8 1.4 1.6

Data on file, Novartis Pharma AG.Cohn JN et al. N Engl J Med. 2001;345:1667-1675.

HF = heart failure.*First hospitalization.Cohn JN et al. Circulation. 2000;102:2672b.

3 6 9 12 15 18 21 24 270

65

70

75

80

85

90

95

100

Months

Event-Free Probability

P < 0.00001

27.5% Risk Reduction

0

ValsartanPlacebo

HF-Related Hospitalizations*HF-Related Hospitalizations*

30

Congestive Heart Failure Dr Bernard Silke, MD, DSc, FRCP, Cardiovascular Physician, St. James’...

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